The human APP protein has been isolated and fully characterized (Kang, et al., Nature 325:733–436 (1987), designated hereinafter as “APP-695”)). This protein contains a segment (the “RERMS” domain) that protects neurons from injury associated with ischemia and that promotes neuronal growth (Bowes, et al., Exp. Neurol. 129:112–119 (1994)). The present invention is based upon the discovery that certain regions within APP, distinct from the RERMS domain, are also cytoprotective. These regions were identified based upon their homology to the iron oxidase domain of ferritin.
The H-ferritin iron oxidase domain is believed to protect vascular endothelial cells from damage caused by iron-catalyzed production of toxic hydroxyl radicals (Balla, et. al., J. Biol. Chem. 267:18148–18153 (1992); Juckett, et al., Am. J. Pathol. 147:782–789 (1995); Balla, et al., Am. J. Physiol. 268:321–327 (1995)). Mutations at specific sites in the ferritin heavy chain (particularly those affecting Glu63 and His66) result in a loss of oxidase activity and render the protein completely ineffective as a cytoprotectant (Lawson, et al., Nature 349:544 (1991)); Balla, et al., Am. J. Physiol. 268:L321–327 (1995)). It has been suggested that ferritin provides a locally trophic environment, promoting cellular growth in the vicinity of iron-catalyzed oxidative damage (Terada, et al., Iron and Human Disease, R. Lauffer, ed., pp. 313–329 (1992)). Proteins and peptides homologous to the iron oxidase domain of ferritin would be expected to have a similar effect and to be useful in preventing oxidative damage associated with reperfusion subsequent to a stroke or heart attack (Davalos, et al., Neurology 54:1568–1574 (2000)).